Cryosurgery is a procedure for destroying tissue. In cryosurgery, undesirable tissues are frozen and destroyed. The technique is minimally invasive, usually requiring an insertion of one or more thin, cylindrical, cryosurgical probes into the undesirable tissue. The probes are cooled internally with a cryogen and are insulated except at the tip. The uninsulated tip is inserted in a tumor or other undesirable tissue, and the tissue is frozen from the probe surface outward. When the desired amount of tissue has been frozen, cryogen is prevented from flowing to the probe, and the tissue is allowed to thaw. After cryosurgery, the frozen tissue is left in situ to be reabsorbed by the immune system over time.
Since freezing originates from the small uninsulated tip of a probe, cryosurgery can be confined to a region of the diseased tissue, thereby sparing surrounding healthy tissue. The freezing process can be precise and controlled, as the freezing interface is sharp and propagates slowly (in the order of mm/min). A small probe having a diameter of around 3 mm can produce a 3.5 cm ice ball, and therefore treat a relatively large tissue region. When the shape of the pathological tissue is large and complex, several probes can be used simultaneously to generate a frozen region of a desired shape. For example, prostate and liver cryosurgery is currently performed with five 3 mm diameter probes. Multiple sites can be treated separately or together. Because the only physical invasion of the tissue is the insertion of the cryoprobes, cryosurgery does not create a lot of complications, and patient morbidity is low. Cryosurgery can produce excellent medical results with less distress and disfiguration at a lower cost. In addition, cryosurgery is not dose limited, therefore retreatment is possible.
Until recently, a major impediment to the extensive use of cryosurgery on internal tissues has been the inability to observe the frozen region deep inside the body, which could cause complications of over or under freezing. Breakthroughs in non-invasive imaging technology, however, have made possible major advances in cryosurgery in general, and prostate and liver cryosurgery in particular. Intraoperative ultrasound can image the process of freezing during cryosurgery by virtue of the fact that the interface between frozen tissue and non-frozen tissue is associated with a change in acoustic impedance that reflects ultrasound waves. Cryosurgery is now almost universally carried out under ultrasound guidance. Another recent improvement in imaging technology for use with cryosurgery is magnetic resonance imaging. This technique, which images the process of freezing in three dimensions, can monitor the freezing interface with a resolution of 200 micrometer, and can control its shape through magnetic resonance feedback. Additional methods of imaging are being continuously developed. One such method under development is the use of light to image freezing. Cryosurgery can be performed with greater accuracy and control with the assistance of the imaging techniques. Therefore, cryosurgery is gaining acceptance as a first-line therapy for prostate, liver and other cancer therapy.
While advances in imaging have provided the means to accurately monitor and control the extent of freezing during cryosurgery, the ability to image the extent of freezing have revealed the existence of new problems. The problems relate to the fact that during cryosurgery, healthy tissues, nerves, or blood vessel are being frozen either accidentally or because of constrains in the placement of cryosurgical probes. For example, destruction of healthy tissues or nerves can cause incontinence or impotence in prostate cryosurgery. Prostate cryosurgery typically uses five cryosurgical probes placed around the urethra. This causes an ice ball to form around the urethra. While it is desirable to freeze prostate tissue that is located close to the urethra to completely destroy a prostate tumor, the urethra itself cannot be frozen because this will induce significant complications such as sloughing and incontinence. An existing solution to this problem is to introduce a heating device in the urethra during prostate cryosurgery to protect the urethra from freezing. Similarly, it is desirable to freeze prostate tissue located close to the rectum during cryosurgery. However, freezing the rectum itself produces major complications. While rectal ultrasound monitoring has significantly reduced the probability of inadvertently freezing the rectum, situations in which the rectum is frozen accidentally still occur. It is also important not to freeze the nerve bundle which connects to the penis and passes through the prostate during prostate cryosurgery. Destruction of the nerves by freezing can lead to impotence. Therefore, surgeons are faced with the dilemma of choosing between destroying all the prostate tumors as close as possible to the nerves, while risking impotence or destroying less prostate tissue to preserve potency while risking survival of malignant tissue.
Similar problems exist with cryosurgery of other body parts. During liver or other organ cryosurgery where tumors are located close to large blood vessels, it is important to freeze the tumors as close to the blood vessels as possible, without damaging the blood vessels themselves. During brain cryosurgery, it is important to avoid freezing of regions of sensitive tissue. In cryoliposuction, there is a need for protecting the outer appearance of the skin while freezing the fatty tissue close to the skin. These examples illustrate that a challenge to cryosurgery is in protecting certain healthy tissues either within or around a malignant or unwanted tissue region, while destroying the malignant or unwanted tissue region during cryosurgery.
Much of the research on the effects of freezing on biological materials has focused on the use of freezing for preservation of cells (such as red blood cells, embryos, sperm). This work has shown that an important thermal variable is the cooling rate (change in temperature per unit time) during freezing. The correlation between cell survival and cooling rate is an "inverse U" shape. Cell survival is greatest for the cooling rate at the peak of the inverse "U", and destruction increases above or below this optimal cooling rate for survival. However, different types of cells have different optimal cooling rates for survival. This difference is associated with the structure and mass transfer properties of the cell membrane and the size of the cells. These general findings are incorporated in Mazur's "two factor" theory, which explains how cooling rates relate to cellular damage.
Mazur proposed that since the probability of an ice crystal forming at any temperature is a function of volume during freezing of cells in a cellular suspension, ice forms first in the much larger extracellular space, before each individual cell freezes. Since ice does not incorporate solutes, the ice that forms in the extracellular space rejects the solutes into the remaining unfrozen solution. The concentration of solutes in the extracellular solution consequently increases. The small volume of intracellular solution results in a correspondingly low probability for ice nucleation to occur inside the cell. Therefore, with sufficiently low cooling rates, the intracellular solution can remain supercooled and unfrozen, when the extracellular solution begins to freeze and exclude solutes. Under these circumstances, the unfrozen cells become surrounded by a hypertonic solution. To equilibrate the difference in chemical potential between the intracellular and the extracellular solution, water passes through the cell membrane, which is permeable to water but impermeable to ions and other organic solutes. Therefore, as the temperature of the solution is lowered and additional ice forms in the extracellular solution, water leaves the cell to equilibrate the intracellular and the extracellular concentration, and the cell dehydrates and shrinks. The intracellular solution remains unfrozen and become hypertonic, causing chemical damage involving denaturation of intracellular proteins. Since chemical damage is a function of time and temperature, the damage increases with lower cooling rates. Because water transport is a rate dependent process, faster freezing with higher cooling rates decreases the amount of time a cell is exposed to the chemically damaging conditions and increases survival. This explains the increase in cell viability with an increase in cooling rate toward an optimum. However, increasing the cooling rate also results in a more rapid decrease in temperature. The unfrozen water in cells therefore experience a greater thermodynamic supercooling. The supercooled intracellular solution is thermodynamically unstable, and after reaching a certain value it nucleates and freezes. It is thought that the intracellular ice formation damages cells. The probability of intracellular ice formation increases with increasing cooling rate, and consequently the survival of frozen cells decreases with increasing cooling rate.
These two modes of damage, chemical at low cooling rates and intracellular ice formation at high cooling rates, form the basis of the "two factor" theory of cellular damage proposed by Mazur. Survival of cells is optimal during freezing with thermal conditions in which these two conflicting modes of damage are minimized.
Based on this fundamental knowledge of the effects of thermal variables on survival of frozen cells, it has been proposed that controlling the cooling rates during freezing can be used to design optimal cryosurgical protocols. While cryosurgical procedures can be optimized to take advantage of the effects of thermal variables (e.g. cooling rates) on the outcome of freezing, this is difficult to accomplish when the means for control are limited by the number and restricted placement of the cryosurgical probes. With normally only five cryosurgical probes, it is very difficult to control the outcome of cryosurgical procedures through control of thermal history during freezing.
Chemical compounds exist that can protect cells from damage during freezing. These compounds, usually referred to as cryoprotective or cryophylactic agents, are used in cryobiology for protecting cells and organs for preservation by freezing outside a live body.
In 1948, Polge, Smith and Parkes discovered that spermatozoa can be protected from freeze damage by the addition of glycerol. Subsequent studies have shown that compounds such as ethylene glycol, dimethyl sulfoxide, polyethylene glycol, polyvinyl pyridine and others have the ability to protect cells from freeze damage. There are two mechanisms by which cryoprotective agents protect cells from freeze damage. One is intracellular with compounds that protect cells from freeze damage by penetrating into the cells. Examples of such compounds are glycerol and dimethyl sulfoxide. The other is extracellular with compounds that protect the cells from the exterior. An example of such compound is polyvinyl pyridine. With the intracellular mechanism, the compound replaces the water in the cell, and consequently reduces both the reduction of the cell volume during slow freezing by remaining in the cells as the cell dehydrates, as well as the probability of intracellular nucleation during rapid freezing. The protection afforded by the intracellular cryoprotectants is concentration dependent, increasing with the concentration until a maximal value is reached where the chemotoxic effects of the cryoprotectants become damaging to the cells. The extracellular protecting compounds presumably protect the cell by interacting with the outer cell membrane and also by inhibiting the rate of water dehydration. FIG. 1 illustrates the effects of intracellular and extracellular cryoprotective agents on cells during cryosurgery.
An object of the present invention is to develop a cryosurgery method and apparatus, which protects desirable tissue from damage during cryosurgery of unwanted tissue.